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G. M. Maharvi, A. H. Fauq / Tetrahedron Letters 51 (2010) 6542–6544
under a Lewis acid catalysis in high yield.11 In another pot, the sul-
fonamide ester 12 was generated by treating the amino ester 3
with a saturated solution of ammonia in methanol. The alcohol
11 was then coupled with the N-4-chlolrobenzenesulfonyl carbox-
amide 12 using a Mitsunobu protocol that furnished BMS-708163
in 66% isolated yield after silica gel purification.
Acknowledgments
The internal financial support provided for this synthetic pro-
ject by Mayo Foundation is gratefully acknowledged.
References and notes
The synthesis of enantiomeric forms of 3 is known.6,8,12 We at-
tempted an alternative, shorter, and more convenient method to
generate 3, based on Schöllkopf reagent diastereoselective alkyl-
ation.13 Thus, the lithio anion derived from the reagent 13 (Scheme
2) was alkylated at À78 °C in tetrahydrofuran with 1-iodo-3,3,3-
trifluoropropane to give diastereomerically enriched product 14
in low (10%) but with 97% de (Scheme 3). The yield was consider-
ably improved (61%) by using 3,3,3-trifluoropropyl trifluorme-
thanesulfonate as an electrophile, but the diastereomeric
induction dropped to 74% de and the diastereomers could not be
separated by silica gel chromatography. We hoped to separate
the desired R-isomer of 3,3,3-trifluoropropylglycinamide 3a at a la-
ter stage. Therefore, the enriched diastereomeric mixture 14 was
hydrolyzed with 0.15 M aqueous TFA in acetonitrile to afford the
desired enantiomerically-enriched (R)-methyl 3,3,3-trifluorpropyl
glycinate 3a admixed with the (S)-valine methyl ester. Unfortu-
nately, valine ester impurity could not be effectively separated
from the 3a. However, when this scalemic mixture of the two es-
ters was subjected to N-sulfonylation, the enantiomerically-en-
riched methyl sulfonamide derivative (R)-4a could be readily
separated from the corresponding (S)-enantiomer of methyl valine
sulfonamide (overall yield of (R)-4a in three steps from Schöllkopf
alkylation was 43.5%).
1. (a) Wimo, A.; Jonsson, L.; Winblad, B. Dement. Geriatr. Cogn. Disord. 2006, 21,
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Tsuruoka, M.; Niimura, M.; Takahashi, Y.; Thinakaran, G.; Iwatsubo, T. Nature
1998, 438–441; (c) De Strooper, B. Neuron 2003, 38, 9–12; (d) De Strooper, B.;
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acetamide compound as an inhibitor of beta amyloid peptide production. U.S.
Patent Application 2009/0111858 A1, 2009.; Macor, J. E.; Albright, C. F.;
Meredith, J. E.; Zaczek, R. C.; Barten, D. M.; Toyn, J. H.; Slemmon, R.; Lentz, K.;
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Gillman, K. W.; Olson, R. E. Discovery of BMS-708163: A Potent and Selective
Gamma-c-Secretase Inhibitor Which Lowers CSF Beta-Amyloid in Humans.
Presented at the 237th National Meeting of the American Chemical Society, Salt
Lake City, UT, March 22–26, 2009; Abstract MEDI-027.
7. For information on the Phase II trials of BMS-708163, visit: http://
8. For
9. Tsushima, T.; Kawada, K.; Ishihara, S.; Uchida, N.; Shiratori, O.; Higaki, J.; Hirata,
M. Tetrahedron 1988, 44, 5375.
10. Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc. Jpn. 1967, 40, 2380–2382.
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In sum, a concise, convergent racemic synthesis of the APP-
selective, Notch-sparing
c-secretase BMS-708163 has been
achieved in overall reasonable yield. Since the optically pure (
D
)-
3,3,3-trifluoropropylglycinamide is known in the literature,6,8,12
this synthesis of BMS-708163 constitutes a formal chiral synthesis
as well.